74 articles - From Saturday Mar 05 2022 to Friday Mar 11 2022
Guidelines, position statements, white papers, technical reviews, consensus statements, etc…
| Blood |
Expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with emerging role of targeted (BRAF- and MEK-inhibitor) therapies. Despite documented response to treatments, many patients struggle with high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately. |
meta-analyses and systematic reviews
RCT, clinical trials, retrospective studies, etc…
| Am J Hematol |
External Validation of the HIGH-2-LOW Model: A Predictive Score for Venous Thromboembolism after Allogeneic Transplant. High vs low-risk was associated with OR of 2.80 (1.46-5.38) for VTE and 4.21 (1.82-9.77) for PE/LE-DVT at FHCRC, and OR of 3.54 (2.12-5.91) for VTE and 6.82 (2.30-20.16) for PE-LE-DVT at MDACC. The HIGH-2-LOW RAM identified allogeneic HCT recipients at high-risk for VTE in both validation cohorts. It can improve evidence-based decision-making for thromboprophylaxis post-transplant. |
Mantle cell lymphoma in 2022 - A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remains a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing. This article provides a comprehensive update on MCL in 2022. |
Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease. Objective responses were seen in 94% (95% confidence interval [CI]: 73-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52-94%) of them. Progression-free and overall survival were 49% (95% CI: 30-79%) and 61% (95% CI: 40-92%) at 2 |
| Ann Oncol |
| Blood |
Deletion of Grin1 in mouse megakaryocytes reveals NMDA receptor role in platelet function and proplatelet formation. In summary, we provide the first genetic evidence that NMDAR plays an active role in platelet function and production. NMDARs regulate PPF through the mechanism that involves MK-ECM interaction and cytoskeletal reorganization. Our results suggest that NMDAR helps guide PPF in vivo. |
Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis. The inflammatory mediators lipopolysaccharide and interferon gamma increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis. |
Exosomes in Multiple Myeloma: from bench to bedside. Targeting exosome secretion could therefore potentially block these different processes. In this review we will summarize the current findings of exosome-related processes in the BM and describe not only the current treatment strategies to counter them but also how exosomes can be harnessed to deliver toxic payloads. Finally, an overview of the different clinical studies which investigate EV cargo as potential MM biomarkers in liquid biopsies will be discussed. |
HLA-DQ Heterodimers in Hematopoietic-Cell Transplantation. In HLA-DQ-mismatched transplantation for malignant diseases, matching or mismatching for G2 increased relapse risk. G2 lowered disease-free survival after both HLA-matched and HLA-DQ-mismatched transplantation. A paradigm based on HLA-DQ heterodimers provides a functional definition of the hematopoietic-cell transplantation barrier and a means to lower risks for future patients. |
Natural history of PF4 antibodies in vaccine induced immune thrombocytopenia and thrombosis. Only one case had extension of their thrombosis. Overall, despite the persistence of PF4 antibodies in 72% of patients, the rate of relapse is low and does not appear to result in recrudescence of the aggressive clinical picture seen at index presentation. Monitoring of these patients in the UK cohort is ongoing and will aid definition of the natural history of this novel condition. |
Structural insights into collagen-binding by platelet receptor Glycoprotein VI. Alanine-scanning of peptide III-30 also identified two AGPOGP motifs that contribute to GPVI-binding, but steric hindrance between GPVI-molecules restricts the maximum binding capacity. We further show that no cooperative interactions could occur between two GPVI-monomers binding to a stretch of (GPO)5, and that binding of two or more GPVI-molecules to a fibril-embedded helix requires non-overlapping OGPOGP-motifs. Our structure confirms the previously suggested similarity in collagen binding between GPVI and Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR-1), but also indicates significant differences that may be exploited for the development of receptor-specific therapeutics. |
The RIG-I-NRF2 axis regulates the mesenchymal stromal niche for bone marrow transplantation. Genetic inhibition of RIG-I sustained NRF2 protein levels and reduced ROS levels in ATRA-treated BMSCs, thus preserving their clonogenicity, bone-forming ability, and stromal niche function in supporting HSC engraftment in mice. More importantly, RIG-I inhibition recovered the ATRA-treated stromal niche function, to enhance HSC engraftment and emergency myelopoiesis for innate immunity against the bacterium Listeria monocytogenes during transplantation. Overall, we identified a non-canonical role of RIG-I in the regulation of the stromal niche for HSC transplantation. |
Treatment and Clinical Endpoints in Polycythemia Vera: Seeking the Best Obtainable Version of the Truth. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis, as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia, and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV. |
| Blood Adv |
A new role for the SRC family kinase HCK as a driver of SYK activation in MYD88 mutated lymphomas. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells; broaden the pro-survival signaling generated by aberrant HCK expression in response to MYD88Mut; and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas. |
Genetic variants of PKLR are associated with acute pain in sickle cell disease. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4 - rs2071053; intron 2 - rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using p<0.0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined. |
SAXS analysis of the intrinsic tenase complex bound to a lipid nanodisc highlights intermolecular contacts between factors VIIIa/IXa. Our results highlight multiple points of contact between fVIIIa and fIXa, including a novel interaction with fIXa at the fVIIIa A1-A3 domain interface. Lastly, we identified hemophilia A/B-related mutations with varying severities at the fVIIIa/fIXa interface that may regulate Xase complex assembly. Together, our results support the use of SAXS as an emergent tool to investigate the membrane-bound Xase complex and illustrate how mutations at the fVIIIa/fIXa dimer interface may disrupt or stabilize the activated enzyme complex. |
| Blood Cancer J |
Identification of the estrogen receptor beta as a possible new tamoxifen-sensitive target in diffuse large B-cell lymphoma. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients. |
Preclinical studies of Flonoltinib Maleate, a novel JAK2/FLT3 inhibitor, in treatment of JAK2V617F-induced myeloproliferative neoplasms. FM exhibited strong inhibitory effects on fibrosis of the spleen and bone marrow. Long-term FM treatment showed good pharmacokinetic/pharmacodynamic characteristics with high drug exposure in tumor-bearing tissues and low toxicity. Currently, FM has been approved by the National Medical Products Administration of China (CXHL2000628), and this study will guide clinical trials for patients with MPNs. |
secDrug: a pipeline to discover novel drug combinations to kill drug-resistant multiple myeloma cells using a greedy set cover algorithm and single-cell multi-omics. Next, we performed single-cell proteomics (CyTOF or Cytometry time of flight) in patient-derived bone marrow cells (ex vivo), genome-wide transcriptome analysis (bulk RNA sequencing), and functional assays like CRISPR-based gene editing to explore molecular pathways underlying secDrug efficacy and drug synergy. Finally, we developed a universally applicable R-software package for predicting novel secondary therapies in chemotherapy-resistant cancers that outputs a list of the top drug combination candidates with rank and confidence scores. Thus, using 17AAG (HSP90 inhibitor) + FK866 (NAMPT inhibitor) as proof of principle secDrugs, we established a novel pipeline to introduce several new therapeutic options for the management of PI and IMiD-resistant myeloma. |
Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989-2018. These findings were congruent across al studied stage groups. Five-year RS across the three age groups during 2011-2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II-IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches. |
| Haematologica |
Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockage of NOTCH activation by b-Secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the pro-tumorigenic role of EV in MM as well as other tumors. |
High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL. Among MRD+ patients, 91% had a MRD >0.01% before blinatumomab, and 89% achieved a complete MRD response after blinatumomab. High preblinatumomab MRD levels were associated with shorter RFS (p=0.049) and OS (p=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between 0.1-1%, and. |
The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition. We highlighted that while IL32ß-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFNB inhibition to counteract microenvironment-dependent induction of IL32ß and BAFF-dependent survival of MCL cells. This data uncovered the IL32ß/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophages polarization and tumor survival, which could be counteracted through selective NIK inhibition. |
| J Hematol Oncol |
Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial. MSCs plus second-line treatments increase the efficacy of SR aGVHD, decrease drug toxicity of second-line drugs and cGVHD without increasing relapse, and are well-tolerated. MSCs could be recommended as a second-line treatment option for aGVHD patients. |
| Lancet Haematol |
Resuscitation with blood products in patients with trauma-related haemorrhagic shock receiving prehospital care (RePHILL): a multicentre, open-label, randomised, controlled, phase 3 trial. Further research is required to identify the characteristics of patients who might benefit from prehospital transfusion and to identify the optimal outcomes for transfusion trials in major trauma. The decision to commit to routine prehospital transfusion will require careful consideration by al stakeholders. National Institute for Health Research Efficacy and Mechanism Evaluation. |
| Leukemia |
Co-targeting leukemia-initiating cells and leukemia bulk leads to disease eradication. ATRA |
Sirolimus is effective for refractory/relapsed/intolerant acquired pure red cell aplasia: results of a prospective single-institutional trial. Adverse events were recorded in 19 patients, including infections and increase of creatine. Secondary aPRCA with stable underlying diseases had similar results as those with primary aPRCA. In summary, sirolimus is effective for patients with refractory/recurrent/intolerant aRPCA with a low recurrence rate and toxicities. |
| Thromb Haemost |
Aspirin for Primary Cardiovascular Prevention in Patients with Diabetes: Uncertainties and Opportunities. Obesity, which is frequently associated with diabetes, also impacts its pharmacokinetics via an increase in distribution volume. Small-scale pharmacokinetic and pharmacodynamic studies have suggested that the relative aspirin resistance phenotype observed in patients with diabetes may be reversed with a twice-daily dosing schedule, and with nonenteric-coated aspirin formulations. Properly powered randomized controlled trials investigating the efficacy and safety of aspirin dosing schedules and formulations tailored to the population of patients with diabetes are urgently required to optimize patient care. |
Assessing clinically meaningful hypercoagulability after COVID-19 Vaccination: a longitudinal study. No relevant differences were detected in platelet count and aggregation, or thromboelastometry parameters. No thrombotic or haemorrhagic events occurred. We can confirm that no clinically meaningful hypercoagulability occurred after either vaccine, albeit keeping in mind that thrombin generation may increase in the first days after the second dose of either vaccine and after the first dose of the ChAdOx1 vaccine. |
Cucurbitacins elicit anti-platelet activity via perturbation of the actin cytoskeleton and integrin function. Disruption to cytoskeletal dynamics has been previously shown to impair integrin activation, platelet spreading and clot retraction. Anti-platelet properties of cucurbitacins were found to extend to a disruption of stable thrombus formation, with an increase in thrombi instability and de-aggregation under flow. Our research identifies novel, anti-platelet and anti-thrombotic actions of cucurbitacins that appear to be linked to dysregulation of cytoskeletal dynamics and integrin function. |
GDF-15, hs-TnT and NT proBNP for Predicting Risk of Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy. For NT-proBNP, levels =183.5pg/mL was not associated with VTE. Similar results were observed in the Fine and Gray analysis. Our results indicate that increased GDF-15 and hs-TnT levels predicted increased VTE risk. |
Managing uncertainty: Physicians' decision-making for stroke prevention for patients with atrial fibrillation and intracerebral haemorrhage. Physicians described the process of deciding on stroke prevention in patients with AF post-ICH as 'challenging' due to considerable 'clinical equipoise'. Key factors that affected decision-making was patient comorbidities, functional status, and patient willingness to engage with oral anticoagulation therapy. Shared decision-making was believed to be beneficial, but physicians believed that the ultimate responsibility to decide on stroke prevention lay with the clinician. |
The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonists. BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with VKAs, so it is advisable to monitor the INR shortly after vaccination, even in stable patients. |
Plenty of the editorials are available as full text through the publisher website using the provided link
| Blood |
| J Hematol Oncol |
Circadian rhythms and cancers: the intrinsic links and therapeutic potentials. In this review, we first describe the general regulators of circadian rhythms and their functions on cancer. In addition, we provide insights into the mechanisms underlying how several types of disruption of the circadian rhythm (including sleep-wake, eating-fasting, and activity-rest) can drive cancer progression, which may expand our understanding of cancer development from the clock perspective. Moreover, we also summarize the potential applications of modulating circadian rhythms for cancer treatment, which may provide an optional therapeutic strategy for cancer patients. |
Letters to the editors and authors’ replies
| Am J Hematol |
| Blood Adv |
| J Hematol Oncol |
BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i. e., DT2216, shows synergistic responses and can potentially overcome resistance. |
all remaining publications eg case reports, images of the month, etc…
| Am J Hematol |
| Blood |
| Blood Adv |
| Lancet Haematol |
| Leukemia |